Identification and Validation of Leucine-rich α-2-glycoprotein 1 as a Noninvasive Biomarker for Improved Precision in Prostate Cancer Risk Stratification

Abstract

Background More accurate risk assessments are needed to improve prostate cancer management. Objective To identify blood-based protein biomarkers that provided prognostic information for risk stratification. Design, setting, and participants Mass spectrometry was used to identify biomarker candidates from blood, and validation studies were performed in four independent cohorts retrospectively collected between 1988 and 2015. Outcome measurements and statistical analysis The primary outcome objectives were progression-free survival, prostate cancer–specific survival (PCSS), and overall survival. Statistical analyses to assess survival and model performance were performed. Results and limitation Serum leucine-rich α-2-glycoprotein 1 (LRG1) was found to be elevated in fatal prostate cancer. LRG1 provided prognostic information independent of metastasis and increased the accuracy in predicting PCSS, particularly in the first 3 yr. A high LRG1 level is associated with an average of two-fold higher risk of disease-progression and mortality in both high-risk and metastatic patients. However, our study design, with a retrospective analysis of samples spanning several decades back, limits the assessment of the clinical utility of LRG1 in today’s clinical practice. Thus, independent prospective studies are needed to establish LRG1 as a clinically useful biomarker for patient management. Conclusions High blood levels of LRG1 are unfavourable in newly diagnosed high-risk and metastatic prostate cancer, and LRG1 increased the accuracy of risk stratification of prostate cancer patients. Patient summary High blood levels of leucine-rich α-2-glycoprotein 1 are unfavourable in newly diagnosed high-risk and metastatic prostate cancer.

LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency

“…Vessels from LLC lung metastases (Figure S1C) exhibited a strong induction of Lrg1 compared with normal lung vessels in which the expression was barely detectable (Figures 1J and S1D). Overall, these observations align with our human data and previous reports, [27][28][29][30][31][32][33][34][35][36][37][38][39] and raise the possibility that local secretion of LRG1 may affect the TME of primary and metastatic tumors and, in particular, through both autocrine and paracrine signaling, vascular function.…”

“…LRG1 expression is increased in human cancer patients Under normal conditions, LRG1 is expressed predominantly by the liver, but in cancer there is strong evidence that its expression is significantly induced. [27][28][29][30][31][32][33][34][35][36][37][38][39] To confirm these findings, LRG1 protein was examined by immunohistochemistry in human lung, prostate, and breast carcinomas, with all three exhibiting high expression compared to adjacent normal-appearing tissue or normal control tissue (Figures 1A-1C). We also observed expression of LRG1 in peritumoral endothelial cells (Figure 1D).…”

“…We therefore investigated the combination of LRG1 antibody blockade and adoptive T cell therapy. Following subcutaneous grafting of B16-F10 melanoma cells harboring the internal influenza nucleoprotein antigen NP68 (NP68-B16), 37 donor F5B6 CD8 + T cells expressing a T cell receptor (TCR) specific for the NP68 peptide were transferred to the tumor-bearing host mice. As previously described, 48 F5B6 CD8 + T cells significantly reduced tumor growth (Figures 6A and S5B).…”

LRG1 Expression Is Elevated in the Eyes of Patients with Neovascular Age-Related Macular Degeneration

“…Our data demonstrate unequivocally that LRG1 is produced locally in the nvAMD eye but this does not rule out a potential contribution from the circulating pool. Plasma LRG1 concentration in healthy controls ranges between 10 and 25 µg/mL [26][27][28] and it is possible that the aqueous humor LRG1 levels may be influenced by the diffusion of the protein from the plasma. Therefore, the aqueous humor LRG1 concentration could be influenced by VEGF levels that modulate vascular permeability and, consequently, be indirectly affected by anti-VEGF therapies.…”

LRG1 Promotes Metastatic Dissemination of Melanoma through Regulating EGFR/STAT3 Signalling

“…Neovascularization plays an essential role in tumour expansion [12] and tumour vasculature provides a route of transportation for tumour cell dissemination [13]. Indeed, altered LRG1 expression is associated with various cancers and LRG1 has been proposed as a prognosis/diagnosis marker for hepatocellular carcinoma, gastric cancer, pancreatic cancer, leukaemia, ovarian cancer, breast cancer, prostate cancer, biliary tract cancer, bladder cancer, and non-small cell lung cancer [14][15][16][17][18][19][20][21]. LRG1 regulates tumour angiogenesis by inducing VEGFA through HIF1α activation [22].…”